Fillers and methods for displacing tissues to improve radiological outcomes

ABSTRACT

Certain embodiments include a method of improvising radiological outcomes by introducing a filler to between a first tissue location and a second tissue location to increase a distance between the first tissue location and the second tissue location, and administering a dose of radioactivity to at least the first tissue location or the second tissue location. Collagen and hyaluronic acid are examples of fillers. Certain embodiments include a medical device having a biocompatible, biodegradable filler material, wherein the device comprises at least a portion that has a shape that substantially conforms to Denovillier&#39;s space between the rectum and prostate. Certain embodiments include a kit, the kit comprising a filler and instructions for placing the filler between a first tissue location and a second tissue location to increase a distance between the first tissue location and the second tissue location.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patents60/427,662 filed Nov. 19, 2002, 60/391,027 filed Jun. 24, 2002, and60/444,143, filed Jan. 31, 2003, which are hereby incorporated herein byreference.

BACKGROUND

[0002] Over 198,100 men will be diagnosed with prostate cancer eachyear. Typically, forty percent will choose interstitial implant therapy,one-third of the men will choose surgery, and one third will chooseexternal beam radiotherapy.

[0003] Typical treatments for prostate cancer include surgical removalof the prostate (prostatectomy), freezing the prostate (cryosurgery),hormonal therapy, prostate seed implant therapy, or prostate conformalradiation.

[0004] The treatment providing the best outcome is still debatable.However, the side effects of treating prostate cancer have become lesstoxic and less profound with implant therapy and 3D conformalradiotherapy. Advancements in treatment positioning and targetlocalization have significantly improved outcomes and diminished theside effects.

[0005] Since the conception of 3D conformal radiotherapy, physicianshave paid attention to the delivered dose to the target and surroundingtissues. Investigators have been able to correlate side effects to theamount of tissue receiving a certain radiation dose. This term has beencoined: dose volume histogram. For conformal radiotherapy it isconventionally preferred that the rectum receive less than 40% of theprescribed treatment dose in hopes of minimizing the radiation inducedside effects.

[0006] Time, distance, and shielding affect the dose that is delivered.The less time an area is exposed to radiation, the less dose delivered.The greater the distance from the radiation, the less dose delivered.Finally, more shielding will also decrease the delivered dose.

SUMMARY OF CERTAIN EMBODIMENTS OF THE INVENTION

[0007] It would be desirable to provide a protocol to decrease theradiation dose to the rectum during radiotherapy for prostate cancer. Itis also desirable to decrease radiation treatment-induced side effectson sensitive organs resulting from other therapies and applicationsdirected to a target organ. Certain embodiments of the present inventionaddress these issues.

[0008] Certain embodiments are a medical device, the device having abiocompatible, biodegradable filler material, wherein the devicecomprises at least a portion that has a shape that substantiallyconforms to the space between two tissue locations, e.g., Denovillier'sspace.

[0009] Certain embodiments are a method comprising introducing a fillerto between a first tissue location and a second tissue location toincrease a distance between the first tissue location and the secondtissue location. Further, there maybe a step of administering a dose ofradioactivity to at least the first tissue location or the second tissuelocation.

[0010] Certain embodiments are directed to kits having a filler,instructions for placing the filler between tissues in conjunction witha treatment, e.g., radiation or cryogenics, and an optional deliverydevice.

[0011] Certain embodiments may have a filler material that comprises anextracellular matrix molecule. Certain embodiments may have a fillermaterial that is biodegradable in vivo in less than approximately 90days. Certain embodiments may have at least one therapeutic agent.Certain embodiments may have a buffering agent. Certain embodiments mayhave a total volume or a volume of filler in the range of about 10 toabout 50 cubic centimeters, wither before or after the device or filleris introduced into the patient. An expandable device may be used forfiller, e.g., a balloon or sponge. Or the filler material may comprise asynthetic polymer.

BRIEF DESCRIPTION OF THE FIGURES

[0012]FIG. 1 depicts the male prostate, rectum and Denovillier's spacebetween the prostate and rectum.

[0013]FIG. 2 depicts the insertion of a needle into the space betweenthe prostate and rectum for injecting collagen therein.

[0014]FIG. 3 depicts the injected collagen within Denovillier's spacebetween the prostate and the rectum.

[0015]FIG. 4 depicts a computer tomography (CT) image of a patient'spelvis showing a collagen filler placed between the prostate and rectumof the patient.

DETAILED DESCRIPTION

[0016] Certain embodiments of the invention comprise placing a fillerbetween the radiation target tissue and other tissues. The fillerincreases the distance between the target tissue and other tissues sothat the other tissues receive less radiation. In some embodiments, thefiller is a degradable material that is installed once prior to thecourse of radiation treatment and does not require subsequentmanipulation, repositioning, or removal. Some fillers maintain theirnatural properties during and after exposure to radiation and remain inthe same location until after a treatment course has concluded. Otherembodiments include fillers made with inflatable devices that areintroduced between the target tissue and other tissue; such inflatabledevices may be left in the patient during the course of radiationtreatment or removed and reintroduced periodically during the course ofradiation treatment. Certain of the embodiments set forth herein addressvarious advantages that are described in the context of the evolution ofthe prostate treatment procedures.

[0017] The modern era has witnessed the evolution of radicalprostatectomy, external beam radiotherapy and interstitial permanentseed Brachytherapy to a point where the results are nearly equivalent.Although some authors may debate that their technique has achievedsuperior results, by and large the results have been too close to claimthat one modality is definitely superior to the other. If this is so,then the decision for therapy must consider treatment related sideeffects.

[0018] External beam radiotherapy may cause radiation-induced sideeffects for prostate cancer. Modern radiation treatment using 3Dconformal therapy and most recently, intensity modulated radiotherapy(IMRT) has significantly reduced treatment related side effects.However, such treatments continue to require special consideration forthe rectum, which is particularly sensitive to radiation. Care is takento ensure that the rectum receives a dose that is well tolerated anddiminishes the probability of treatment related side effects. Othershave evaluated the effectiveness of daily insertion of rectal cathetersand daily administration of rectal radioprotectants, and have achievedonly modest success.

[0019] Some investigators are attempting to decrease the dose to theanterior rectal wall and thereby decrease the potential for radiationinduced side effects on the rectum. One such technique is to insert aninflatable Foley catheter into the rectum on a daily basis duringradiation treatments. The premise is that more of the rectum isdisplaced away from the prostate than the small portion of rectum thatis pushed toward the prostate. Therefore a smaller amount of rectum isreceiving radiation and consequently the side effects from radiationshould be diminished.

[0020] However, certain embodiments set forth herein have advantagesthat may include the reduction of radiation side effects, improved costeffectiveness, the need to perform only one or a few procedures toachieve a reduction in radiation, no requirement for removal of thetreatment after its administration, and ease of use, e.g., by a patient,nurse, or technician.

[0021] Example 2 includes a study that shows that injection of humancollagen into Denovillier's space can change the radiation dose that therectum receives when the prostate is exposed to radiation.“Denovillier's space” is a region located between the rectum andprostate. The collagen was well tolerated and withstood the radiationtreatments. The collagen degraded in less than about sixty days andrequired no procedures after its initial introduction into the patients.The study was a trial involving 10 men who received human collageninjections into Denovillier's space to displace the rectum away from theprostate prior to proceeding with their radiotherapy. The injectionswere well tolerated and could readily be performed on an outpatientbasis. The radiation dose to the rectum was diminished by overapproximately 50% when 20 cc's of human collagen was injected intoDenovillier's space. Moreover, men who have received human collageninjections appeared to have minimal rectal side effects associated fromtheir radiotherapy and had no appreciable changes associated due to thecollagen.

[0022] This procedure was well-tolerated by the patients. Indeed, othershave reported that human collagen has been used in various body areasand is well tolerated. For example, it has been injected into a theperineum in hopes of improving urinary incontinence. And human collagenhas received United States Food and Drug Administration approval to beused in brachytherapy procedures as a spacer. Further, it is known thatnormal saline may be injected into the potential space between therectum and prostate prior to proceeding with cryotherapy to minimize thefreezing effect on the rectum, so displacement of the tissues aroundDenovillier's space is known to be well-tolerated.

[0023] The successful use of collagen as a filler shows that othermaterials may also be used. Other materials may include natural orsynthetic materials, e.g., proteins, extracellular matrix molecules,fibrin, proteins, hyaluronic acid, albumin, bulking agents, andpolyethylene glycol-based materials. A synthetic material is a materialthat is not found in nature.

[0024] Certain embodiments provide a method of displacing a tissue toprotect the tissue against the effects of a treatment involvingradiation or cryotherapy. One embodiment involves using a filler todisplace the tissue relative to a tissue that is to receive thetreatment. Another embodiment involves introducing a filler to displacea first tissue and radiating a second tissue, particularly a secondtissue that is close to the first tissue. In another embodiment, themethod comprises the steps of injecting a filler into a space betweentissues; and may further include irradiating one of the tissues so thatthe other tissue receives less radiation than it would have in theabsence of the filler.

[0025] Certain embodiments also provide methods for treating a tissue ofa body by radiation. In one embodiment, the method comprises the stepsof injecting an effective amount of a filler into a space between afirst tissue (e.g., prostate) of a body and a second tissue (e.g.,rectum), which can be a critically sensitive organ; and treating thefirst tissue by radiation whereby the filler within the space reducespassage of radiation into the second tissue. Tissue is a broad term thatencompasses a portion of a body: for example, a group of cells, a groupof cells and interstitial matter, an organ, a portion of an organ, or ananatomical portion of a body, e.g., a rectum, ovary, prostate, nerve,cartilage, bone, brain, or portion thereof.

[0026] Also provided are embodiments for displacing a sensitive bodytissue relative to another body tissue that is the target of a treatmentprotocol, to effectively reduce side effects on/in the sensitive tissueinduced by or resulting from a treatment directed to the target tissue.In one embodiment, the method comprises injecting a filler into a spacebetween the sensitive body tissue (e.g., rectum) and the target bodytissue (e.g., prostate); and conducting a treatment protocol on thetarget body tissue whereby the sensitive body tissue is less affected bythe treatment as a result of the presence of the filler.

[0027] Examples of embodiments of the treatment include use with suchapplications as external beam radiotherapy (e.g., 3D conformal orIntensity Modulated Radiotherapy), interstitial prostate brachytherapy(e.g., using permanent or temporary seeds, or using High Dose Rateremote after loading), and cryosurgery. Another embodiment is the use ofthese techniques for brachytherapy radiation treatments for prostatecancer or gynecological cancers. Brachytherapy includes the placement ofa radioactive isotope within or near the tumor, target organ, or othertissue. For example, a brachytherapy technique is placement of permanentI-125 radioactive seeds into the prostate for treatment of prostatecancer. Applications for gynecology include embodiments involvingdisplacing a tissue from another tissue that is to be targeted byradiation.

[0028] A filler is a substance that occupies a volume after itsintroduction into a body. Examples of fillers include but are notlimited to polymers, gels, sols, hydrogels, sponges, bulking agents, andballoons. Filler materials include polysaccharides, alginate, collagen,gelatin, fibrin, fibrinogen, albumin, serum, autologous serum, sutures,and natural and synthetic polymers. Synthetic polymers includepolylactide, polyglycolide, polycaprolactones, poly(alpha.-hydroxyacid), poly(amino acid), and poly(anhydride). Fillers may be crosslinkedor uncrosslinked. Polymers include polyethylene glycol and derivativesthereof, including crosslinked polyethylene glycols. Other types ofpolymers include thermoreversible and thixotropic polymers. Otherexamples of a filler include self-absorbing suture material held withina suspension (such as prolene sutures).

[0029] Fillers may include materials that are formed in situ in thebody, e.g., by combining a first precursor and a second precursor toform a material, e.g., a gel or hydrogel. Examples include covalentbonding of electrophiles and nucleophiles (e.g., see U.S. Pat. No.5,874,500) and gelation of polysaccharides (e.g., addition of calcium toalginate). Fillers may include materials derived from the body thatreceives them, e.g., autologous serum. Donor blood may be used to derivesome materials, e.g., albumin. Combinations of materials are alsocontemplated.

[0030] Suitable fillers and materials for fillers may include, forexample, those set forth in U.S. Pat. Nos. 6,509,031; 6,413,742;6,388,047; 6,280,772; 6,271,278; 6,268,405; 6,129,761; 6,031,148;6,110,484; 5,932,539; 5,874,500; 5,863,984; 5,865,367; 5,759,583;5,618,563; 5,599,552; 4,970,298; 4,703,108; and 4,193,813, which arehereby incorporated by reference in their entirety herein.

[0031] Fillers may be biodegradable, either by hydrolysis, proteolysis,the action of cells in the body, or a combination thereof.Biodegradation may be measured by palpitation or other observations todetect the change in volume of a filler after its introduction into apatient. Biocompatible materials are preferred, especially collagen orhyaluronic acid. A suitable length for biodegradation to occur isbetween one day weeks and twelve months after introduction of the fillerinto the body. Alternatively, fillers may remain in place for otherperiods, including from one week to three months and two to eight weeks.Also the filler may be biodegraded in less than about two months afterimplantation, as is preferable for the case of displacing rectal tissuefrom the prostate gland. The time for biodegradability for a specificuse may be determined by the time required to complete a course ofradiation, which may vary for different radiological applications anddifferent requirements for administering the full course of radiologicaltherapy.

[0032] Fillers may include osmotic agents. For example, agents thatincrease the osmotic pressure of the filler may be used in the filler.One advantage of an osmotic agent is that it will cause the filler toincrease its volume after its introduction into the body. For example,albumin, human serum, human plasma, salts, or steroids may be added to,or mixed with, the filler.

[0033] Fillers may contain drugs or be used to deliver drugs. Forexample, a steroid may be introduced into the filler. Drugs may include,for example, steroids, anti-inflammatory agents, agents to inhibitdegradation of the filler (e.g., protease inhibitors), agents to enhancefiller degradation, antibiotics, hemostatics, and antimycotics.

[0034] Fillers may also be reversibly introduced. For example, athermoreversible polymer may be introduced as a liquid-like material andallowed to form a gel in situ. Or a polymer may be introduced that isnon degradable or poorly degradable until it is heated to cause itsdegradation or liquefaction.

[0035] A filler may have a first physical state before its introductioninto the body and a second physical state after its introduction intothe body. A change in physical state may include, for example, a changein volume, viscosity, water content, swelling, or crosslinking. Anotherembodiment is a filler that exists as at least two precursors beforeintroduction into the body and exists as a crosslinked material formedby the mixing of the two precursors after introduction into the body.

[0036] For example, solutions containing collagen or collagen-likeprecursors may be introduced into the body. As the solution warms to thebody temperature as the pH of the solution becomes adjusted to bodilypH, the fibrils cooperate to form a fibrin gel according to well-knownprocessed of collagen formation. The solution has a low viscosity whilestored, e.g., as part of a kit, but has a stronger physical structureafter its self-assembly in situ in the patient.

[0037] And for example, solutions of polysaccharides may be introducedinto the patient. Some polysaccharides increase in viscosity whenexposed to certain salts, or in response to a change in pH. Products andprocesses involving, for instance, hyaluronic acid solutions orprecursors that gel after introduction into a patient are known.

[0038] A solution that contains a filler gels in response to a change inpH may be made up at a first pH in solution, but be buffered so that itspH changes after introduction into a patient. The buffer could berelatively weak compared to physiological buffer saline solutions, or itcould be concentrated. In either case, the buffer would eventuallydiffuse away so that the pH of the filler would be changed.

[0039] Similarly, a solution having a filler that changes viscosity,crosslinks, or gels in response to a change in temperature could beintroduced at a first temperature and allowed to transition to bodytemperature in situ in a patient so that it would have a change inproperties.

[0040] Fillers may be mixed with salts, buffers, or otherpharmaceutically acceptable agents, e.g., carriers. Examples of suitablepharmaceutical carriers are described, for example, in “Remington'sPharmaceutical Sciences” by E. W. Martin. Examples of buffers includephosphates, carbonates, and Tris. Examples of buffer osmolarity areranges from 10 to 3000, from 50 to 600, from 150 to 500, and from300-350. A buffering agent may be both a buffer and an osmolarity agent.Fillers may also be mixed with agents to aid their visualization bymedical devices, e.g., by MRI or ultrasound. Fillers may also be mixedwith agents that block radiation.

[0041] If the filler contains collagen, the collagen may be natural orsynthetic collagen, and of human origin or non-human origin, such asbovine collagen (e.g., Bovine Type I collagen), for example. Thecollagen can be prepared as a suspension with a pharmaceuticallyacceptable vehicle or carrier (e.g., water) having a pH in thephysiological range. Collagen may be collagen derived from a naturalsource, and may includes collagen isolated from tissue and recombinantlyderived collagen, e.g., collagen produced by genetically engineeredbacteria. Collagen may also be collagen that is not found in nature,e.g., materials intelligently designed to mimic collagen or some of thestructural or functional features of collagen.

[0042] Other examples of fillers are hyaluronic acid, cellulose,alginate, and gelatin, which are available from commercial sources,e.g., Sigma-Aldrich, Inc. and ICN Biomedicals, Inc. Hyaluronic acid is amaterial that is accepted in the medical community as a material thatmay be implanted into a patient; other commercial sources are GenzymeAdvanced Biomaterials (e.g., HyluMed®), LifeCore Biomedical, and FMCBioPolymer. Another example of a filler is cellulose, e.g., Avicel® athixotropic cellulose product from FMC BioPolymer. Another fillerexample is synthetic polymer hydrogels, e.g., as made by AngiotechPharmaceuticals, e.g., Coseal®. Other fillers are described in, e.g.,U.S. Pat. No. 6,224,893, and other references set forth herein.

[0043] Another embodiment is a filler that comprises a device having areversible volume, for example, a balloon. A balloon may be introduced,inflated, and then deflated after a dose of radiation has beenadministered, or recovered after the radiation treatment has beencompleted.

[0044] In use, a device for delivering a filler to a body may be loadedwith a filler, and the filler introduced into the body, preferably sothat the distance between a first and a second tissue in the body isthereby increased. A further step may include administering a dose ofradiation to a tissue, preferably so that the second tissue receivesless radiation than it would have received if the distance between thefirst and second tissue had not been increased. A further step may alsobe administration of cryogenic treatment to the first or second tissueor a tissue nearby. The radiation may alternatively be directed to athird tissue so that the first tissue or the second tissue received alower amount of radiation as a result of its separation from the othertissue(s). The first tissue and the second tissue may be adjacent toeach other in the body, or may be separate from each other by othertissues. In many cases, such separation does not reduce the beneficialeffects of achieving separation between the first and second tissue.

[0045] Filler volumes for separating tissues are dependent on theconfiguration of the tissues to be treated and the tissues to beseparated from each other. In many cases, a volume of about 20 cubiccentimeters (cc's or mls) is suitable. In other embodiments, as littleas 1 cc might be needed. Other volumes are in the range of 5-1000 cc,and all ranges therebetween, e.g., 5-400 cc, 10-30 cc, 15-25, cc, 10-150cc, 20-200 cc, 15-500 cc, 50-1000 cc, and 30-200 cc. In someembodiments, filers are administered in two doses at different times soas to allow the tissues to stretch and accommodate the filler andthereby receive a larger volumes of filler than would otherwise bereadily possible.

[0046] An example of a delivery device is a syringe. The filler isloaded into the syringe and injected through a needle into a body.Another example is a device that accepts, e.g., a folded, deswelled, orrolled filler and provides a propelling mechanism to propel the fillerthrough a needle or catheter into a body. Propulsion may be by, e.g., ahandle, a plunger, gas, or liquid force.

[0047] Another embodiment is a kit for introducing a filler into a body.The kit may include a filler and a device for delivering the filler tothe body. The filler may be capable of undergoing a change in stateafter its introduction into the body: for example, a collagen solutionforms a collagen gel after entering the body, and a dehydrated spongeimbibes water to increase its volume after exposure to physiologicalconditions. Embodiments include instructions for use. Embodimentsinclude anesthetics mixed with the filler or separate therefrom.Embodiments include kits wherein the delivery device is a syringe, andother embodiments include a needle for the syringe, and may include aneedle for administering the filler and/or the anesthetic.

[0048] Instructions may be included with a kit. Instructions may includewords that direct a user in a use of a kit. Instructions may be fully orpartially included with the kit, including as an insert, on a label, ona package, in a brochure, a seminar handout, a seminar display, aninternet teaching course, or on an internet or intranet web site. Forexample, a label on a kit could reference an internet address havinginstructions. Instructions may include explanations of embodiments setforth herein. Instructions may include dose histograms, and explanationsof suitable filler volumes for use.

[0049] Preferred anesthetics are local anesthetics, particularly 1%lidocaine for use in applying a filler to a body to displace the rectumfrom the prostate gland. The lidocaine may be used to perform a nerveblock. A preferred needle for anesthetic application is a short 22-gaugeneedle and a 7 cm 22-gauge spinal needle. A preferred needle fordelivering a filler via syringe injection is an 8-gauge spinal needlethat is 3.5 cm length. Kist may include anesthetics.

EXAMPLE 1 Sample Protocol

[0050] This example describes a protocol for reducing the radiationexposure of a tissue by increasing the distance between the tissue and anearby tissue that is to be target for radioactive treatment. Thisexample is cast in terms of using a space between the rectum andprostate, but any two tissues, or portions thereof, may be separated byfollowing this protocol and introducing the filler between the tissuesinstead of into Denovillier's space. Human collagen is used as thefiller, but other fillers may be substituted.

Protocol

[0051] a) Inject human collagen into the space (Denovillier's space)between the rectum and prostate.

[0052] b) Administer an effective volume of human collagen intoDenovillier's space to decrease the radiation dose to the rectum duringradiation therapy of the prostate, and change the rectal dose volumehistogram.

[0053] c) Assess the effectiveness of human collagen in lowering thedose of radiation to the rectum during prostate radiation therapy.

[0054] d) Evaluate the acute side effects of radiation during therapycompared to historical controls.

Patient Eligibility

[0055] a) Male with biopsy-proven prostate cancer.

[0056] b) Age:>18 years of age.

[0057] c) Elected conformal radiotherapy for cure or for palliation,i.e., local control due to known metastases.

[0058] d) Suitable to undergo a transrectal ultrasound for determinationof space between rectum and prostate.

[0059] e) Suitable to receive a local anesthetic prior to receiving thehuman collagen injection.

[0060] f) Tolerated a subcutaneous injection of human collagen to ruleout hypersensitivity to the collagen products.

[0061] g) Signed a study specific consent form.

Patient Contraindications

[0062] a) Allergic to human collagen injection.

[0063] b) Does not tolerate human collagen injection for any reason.

Protocol Treatment—Methods and Materials

[0064] A. Prior to proceeding with the collagen injection, a diagnosticCT scan of the pelvis or a planning CT scan of the pelvis will beperformed with the patient in the supine treatment position. Prior toobtaining the planning CT scan, a Foley catheter will be inserted intothe bladder and drained. Fifty cc's of 50% diluted Conray will beinstilled into the bladder for visualization. The Foley catheter willthen be removed. Five cc's of 50% diluted Conray will be injected intothe penile urethra and retained with a penile clamp for delineation. Arectal tube will be inserted into the rectal vault. Thirty-five cc's ofdiluted contrast will be injected into the rectal vault for delineation.The planning CT scan of the pelvis will be obtained.

[0065] The outside surface of the prostate, bladder and rectum will becontoured (e.g., computer outlining of organs). The rectal contour willextend from the anal verge up to the rectosigmoid junction or to the topof seminal vesicles, whichever is greater, provided there is adequatepelvic parenchymal space so that minimal radiation dose is delivered tothe upper rectum.

[0066] A complex 3-D isodose treatment plan with a 3-D rectal dosevolume histogram (DVH) will be generated using a conformal six-fieldtechnique. Pre-injection and post-injection measurements will bedetermined between the anterior rectal wall and the posterior border ofthe prostate.

B. Procedure to Place the Filler

[0067] The patient will be placed in the dorsolithotomy position withboth legs up in stirrups. The transrectal ultrasound probe will beplaced within the rectal vault. A syringe with a 20-gauge needle will beused to administer a local anesthetic. Preferably, a nerve block isperformed to the inferior branch of the pudendal nerve using a 7 cm22-guage spinal needle to adminsiter 5 cc of 1% lidocaine to the leftand right para-vesicular region located just laterally of the seminalvesicles. A second syringe with a 16-gauge spinal needle will beinserted into the perineum and rotated to increase the potential spacebetween the rectum and prostate. The same syringe will inject normalsaline into the space between the rectum and prostate to furtherincrease the capacity of this potential space.

[0068] Once the normal saline has been injected, a third syringe with a16-gauge spinal needle will be used to inject a 5-10 mm layer of humancollagen along the posterior wall of the prostate between the prostateand rectum. Once the collagen has been injected into the space betweenthe rectum and prostate, ultrasound images will be obtained to determinethe echogenicity of the collagen as well as to correlate the measuredultrasound volume to the CT obtained volume. All used syringes will bediscarded in a safe manner.

[0069] C. A second planning CT scan of the pelvis with simulation willbe performed after placement of the collagen injection using the sametechnique. A 3-D computer generated isodose treatment plan will begenerated with a rectal DVH. Differences between the rectal DVH's willbe noted.

[0070] D. The patient will than proceed with the conformal radiotherapyto a dose of about 7560 cGy in 42 daily treatment fractions.

[0071] E. During the course of treatment, the patient will be monitoredfor changes in bowel frequency, symptoms of proctitis, and amount ofmedications used if necessary.

[0072] F. A third planning CT with simulation will be performed on thefirst five patients after they have received 15-20 daily radiationtreatments. If there has been no significant reduction in collagenvolume nor significant changes in the rectal dose per the DVH, the thirdplanning CT scan will be discontinued.

[0073] G. A fourth planning CT scan with simulation will be performed onthe last day of treatment. Again, a 3-D complex computer plan will begenerated to determine the rectal DVH. Measurements will be compared tothe previous DVH's. If there has been no significant reduction or changein collagen volume nor significant changes in the rectal dose per theDVH, the fourth planning CT will be discontinued after 20 patients.

[0074] H. A fifth planning CT scan with simulation and simulation fordosimetric purposes will be performed approximately 4-6 months aftercompletion of the radiation therapy or 6-8 months after the injection ofcollagen into the space between the rectum and prostate. This scan willbe performed for the first five patients and than discontinued.

Treatment Evaluation

[0075] The results will provide the following information:

[0076] Toleration of injection of human collagen into the space betweenthe rectum and prostate.

[0077] Extent of anterior displacement of prostate from injection ofhuman collagen.

[0078] Amount of radiation dose delivered to anterior wall of rectum.

[0079] Amount of dose reduction to rectum per dose volume histogram(DVH).

[0080] Clinical changes of bowel habits and treatment interventionduring the course of radiation treatments, if any.

Descriptive Factors

[0081] Relationship of cc's of human collagen to forward displacement ofprostate.

[0082] Description of homogeneous distribution of human collagen betweenrectum and prostate as determined per ultrasound and CT scan.

[0083] Relationship of cc's of human collagen to change of rectal dosevolume histogram.

Nursing Evaluation and Treatment Follow-Up

[0084] A weekly assessment of patients will include a review oftolerance of treatment, bowel habit changes and treatment interventions.Typically, medical interventions can include but are not limited toanti-hemorroidal creams/ointments, anti-diarrhea medications,anti-spasmodic medications, alpha-1 inhibitors and analgesics with orwithout narcotics.

[0085] Patient review will be conducted at 2 weeks, 1 month, 3 monthsand 6 months after completion of radiation therapy. The patient willthan be followed on a routine serial basis that is recommended for allcancer patients after receiving radiation therapy. Consistency Normal =N Incontinence Number Soft = S Anti- Anti- of Urine (U) of BM's Hard = HAnal diarrhea Hemorrhoid or per day Loose = 1 Discomfort MedicationMedication Stool (S) Consultation Day 1 of XRT Wk 1 Wk 2 Wk 3 Wk 4 Wk 5Wk 6 Wk 7 Wk 8 2 Weeks 1 Month 3 Months 6 Months 1 Year 1.5 Years 2Years 2.5 Years 3 Years

Human Collagen

[0086] Human collagen is commercially available from multiplemanufacturers. Human collagen has been FDA approved to be injected intopatients and in particular the pelvis and perineurium of humans. The FDAhas also approved the use of human collagen during radiationbrachytherapy. Brachytherapy will deliver a dose that is believed to beimmeasurable at the surface of the radioactive isotope but can rangefrom 300-600 Gy or greater. The traditional radiation dose delivered tothe prostate ranges from 70-76 Gy. However, modern technology using 3-Dconformal radiation or Intensity Modulated Radiotherapy (IMRT) hasallowed dose escalation upwards to 100 Gy. These doses are well belowthe dose of 145 Gy used for brachytherapy or the surface dose of aradioactive isotope.

[0087] Human collagen is typically commercially supplied in preloadedsyringes containing 5 or 10 cc's of collagen. The unit is sterile andcomes sealed. The pack will be stored and inspected for damage prior tobeing opened. If one suspects a damaged product, it will not be used.The human collagen will be removed from its package only prior toundergoing the injection procedure as previously outlined.

[0088] Protocol. A syringe with an anesthetic will be used to obtainlocal anesthesia. A second needle will be inserted into the perineumbetween the potential space between the rectum and prostate. This needlewill be rotated to further open the space between the rectum andprostate (Denovillier's space), and normal saline will then be injectedto further increase this potential space. The human collagen will thenbe injected into this space using ultrasound guidance.

[0089] Once the human collagen has been injected into the perineum asdesired, the used syringes will be discarded in a safe manner.

EXAMPLE 2 Treatment of Ten Males

[0090] This protocol involved injecting an effective volume of humancollagen into Denovillier's space to displace the rectum away fromprostate. A conventional computer plan used for radiation treatmentplanning was used to determine the reduction of dose to the rectum (dosevolume histogram) corresponding to the collagen injection. Accordingly,patients were monitored during their 2 months of radiation treatments toassess acute radiation induced side effects.

[0091] Ten men with stage 1 or stage 2 prostate cancer were informed ofthe ongoing procedure and elected to participate.

[0092] Prior to the collagen injection, each patient underwent a CTsimulation to obtain CT images to be used for a radiation computerintensity modulated radiotherapy (IMRT) treatment plan without humancollagen. All men received their human collagen injection from the sameurologist as an outpatient. To perform the injection, each man wasplaced in the left lateral decubitis position. An ultrasound transducerwas positioned into the rectum so that the entire prostate was wellvisualized. A 7 inch 22 gauge spinal needle was used to perform abilateral pudendal nerve block using 2% lidocaine. After obtainingadequate anesthetic effect, a 5.5 inch 18 gauge spinal needle waspositioned into the space between the rectum and prostate usingultrasound guidance. Once the needle location was believed to be withinDenovillier's space, 5-10 cc's of normal saline was injected to open thepotential space between the rectum and prostate. Real time ultrasoundguidance was used to confirm that the needle was anterior to the rectalwall and posterior to the prostate and therefore within Denovillier'sspace. This process is depicted in FIGS. 1-3, with patient 100 havingspace 102 between rectum 104 and prostate 106 receiving needle 108 intospace 102, with needle 108 being in communication with syringe 110 thatcontains collagen filler 112. The syringe plunger is depressed tointroduce collagen filler 112 into space 102.

[0093] Once it was confirmed that the normal saline was withinDenovillier's space, the protocol proceeded to the injection of humancollagen using the same 5.5 inch gauge 18 spinal needle. Each of the 10men who entered into the protocol received 20 cc's of human collagen.Their prostate volumes ranged from 35 cc up to 90 cc's.

[0094] Following placement of 20 cc's of human collagen, the needle wasremoved and then the ultrasound transducer. Approximately, 5 daysfollowing the collagen injection each man underwent a second CTsimulation to obtain a second IMRT radiation computer treatment planwith the collagen injection. Five days were provided to allowreabsorption of the normal saline and the human collagen to “settle”within Denovillier's space.

[0095]FIG. 4 depicts a CT scan of a man that received a collagen filler.The man 200 received about 20 cc of collagen filler into the space 212between rectum 204 and prostate 206. The space 204 is enlarged so thatthe radiation exposure of rectum 204 is reduced.

[0096] The first and second IMRT radiation computer treatment plans werecompared to evaluate the displacing properties of human collagen andassess the reduction in radiation dose to the rectum. A third IMRTradiation computer treatment plan was obtained on the last day oftreatment to confirm that there had been minimal change throughout theirtreatment.

[0097] During the 2 months of external beam radiation, each person wasinterviewed on a weekly basis. Quality of life issues were assessedregarding their urinary and bowel habits.

[0098] CT scans were obtained 6 months and 12 months followingcompletion of their radiotherapy to monitor absorption of humancollagen.

[0099] Results: Each man who elected to proceed with the ongoingprotocol tolerated the collagen injection very well. No one reportedsymptoms suggestive of an allergic reaction. Three men reported asensation similar to a light rectal pressure that resolved 3-4 hoursafter the injection. One man experienced urinary retention and requiredplacement of a Foley catheter. The catheter was removed 3 days after theinjection without difficulty or recurrence. It is believed that theurinary retention was secondary to the pudendal nerve block.

[0100] All men received prostate treatment to a dose of 75.6 Gy in 42fractions. Their treatment was delivered using an IMRT 6-fieldtechnique. Conventionally, a highly positive outcome is if 30% of therectum receives 45 Gy or less and 10-15% receives 60 Gy or more.

[0101] All of the patients had 20-25% of the rectum receiving 45 Gy orless prior to the collagen injection. Following the collagen injection,7-15% or the rectum received 45 Gy or less. Moreover, <5% of the rectumreceived a dose of 60 Gy or more.

[0102] All men who received a collagen injection prior to theirradiation treatments experienced no change in their bowel habits.Interestingly, one man underwent an unplanned flexible sigmoidoscopy 6months after completing his radiotherapy. His physician who performedthe sigmoidoscopy reported an entirely normal exam without any evidenceof radiation treatments.

[0103] Five of the 10 men experienced urinary frequency, diminishedurinary flow and urgency. Four men elected to be treated with an alpha 1blocker (Flomax) with success.

[0104] The invention has been described in language more or lessspecific as to structural and methodical features and by reference todetailed examples and methodologies. It is to be understood, however,that the invention is not limited to the specific features shown anddescribed, since the means herein disclosed comprise preferred forms ofputting the invention into effect, and the examples are not meant tolimit the scope of the invention. It should be understood thatvariations and modifications may be made while remaining within thespirit and scope of the invention, and the invention is not to beconstrued as limited to the specific embodiments described or as shownin the drawings. All patents, patent applications, journal references,and publications referenced herein are hereby incorporated by referenceherein.

1. A medical device, the device comprising a biocompatible,biodegradable filler material, wherein the device comprises at least aportion that has a shape that substantially conforms to Denovillier'sspace.
 2. The medical device of claim 2 wherein the filler materialcomprises an extracellular matrix molecule.
 3. The medical device ofclaim 2 wherein the extracellular matrix molecule is collagen.
 4. Themedical device of claim 2 wherein the filler material consistsessentially of collagen.
 5. The medical device of claim 1 wherein thefiller material comprises at least one polysaccharide.
 6. The medicaldevice of claim 5 wherein the at least one polysaccharide is hyaluronicacid.
 7. The medical device of claim 1 wherein the filler material isbiodegradable in vivo in less than approximately 90 days.
 8. The medicaldevice of claim 1 further comprising a degradation inhibitor.
 9. Themedical device of claim 1 wherein the filler material is a member of thegroup consisting of alginate, gelatin, fibrin, fibrinogen, albumin,polylactide, polyglycolide, polycaprolactone, poly(alpha-hydroxy acid),polyethylene glycol, thixotropic polymers, thermoreversible polymers,and mixtures thereof.
 10. The medical device of claim 1 furthercomprising a radio opaque marker.
 11. The medical device of claim 1further comprising at least one therapeutic agent.
 12. The medicaldevice of claim 11 wherein the at least one therapeutic agent is amember of the group consisting of an anti-inflammatory drug, anantibiotic, an antimycotics, a hemostat, a steroid, and an analgesic.13. The medical device of claim 1 further comprising an osmotic agentthat causes water to become associated with the filler material byosmosis.
 14. The medical device of claim 1 further comprising abuffering agent.
 15. The medical device of claim 1 wherein the fillermaterial comprises a synthetic polymer.
 16. The medical device of claim1 wherein the device has a volume in the range of 10 to 200 cubiccentimeters.
 17. A method comprising introducing a filler to between afirst tissue location and a second tissue location to increase adistance between the first tissue location and the second tissuelocation, and administering a dose of radioactivity to at least thefirst tissue location or the second tissue location.
 18. The method ofclaim 17 wherein the first tissue location is associated with the rectumand the second tissue location is associated with the prostate gland.19. The method of claim 17 wherein the filler is introduced intoDenovillier's space.
 20. The method of claim 17 wherein the first tissuelocation is located on a tissue that is a member of the group consistingof an ovary, a nerve, a cartilage, a bone, and a brain.
 21. The methodof claim 17 wherein the filler comprises a member of the groupconsisting of alginate, gelatin, fibrin, fibrinogen, albumin,polylactide, polyglycolide, polycaprolactone, poly(alpha-hydroxy acid),polyethylene glycol, thixotropic polymers, thermoreversible polymers,and mixtures thereof.
 22. The method of claim 17 wherein the fillercomprises at least one therapeutic agent.
 23. The method of claim 22wherein the at least one therapeutic agent is a member of the groupconsisting of an anti-inflammatory drug, an antibiotic, an antimycotics,a hemostat, a steroid, and an analgesic.
 24. The method of claim 17wherein the filler is biodegradable in vivo in less than approximately90 days.
 25. The method of claim 17 wherein the filler is an expandabledevice.
 26. The method of claim 25 wherein the expandable device is aballoon.
 27. The method of claim 26 wherein the expandable device is asponge.
 28. The method of claim 17 wherein the filler comprises abiocompatible, biodegradable material.
 29. The method of claim 28wherein the biocompatible, biodegradable material comprises anextracellular matrix molecule.
 30. The method of claim 28 wherein thebiocompatible, biodegradable material consists essentially of collagen.31. The method of claim 28 wherein the filler comprises at least onepolysaccharide.
 32. The method of claim 31 wherein the at least onepolysaccharide is hyaluronic acid.
 33. The method of claim 28 whereinthe filler further comprises a member of the group consisting of adegradation inhibitor, a radio opaque marker, and an osmotic agent thatcauses water to become associated with the filler material by osmosis.34. The method of claim 28 wherein the filler further comprises abuffering agent.
 35. The method of claim 17 wherein the filler comprisesa member of the group consisting of a degradation inhibitor, a radioopaque marker, and an osmotic agent that causes water to becomeassociated with the filler material by osmosis.
 36. The method of claim17 wherein the filler comprises a buffering agent.
 37. The method ofclaim 17 wherein the filler material comprises a synthetic polymer. 38.The method of claim 17 wherein the filler occupies a volume in the rangeof about 10 to about 200 cubic centimeters in a patient.
 39. A kit, thekit comprising a filler and instructions for placing the filler betweena first tissue location and a second tissue location to increase adistance between the first tissue location and the second tissuelocation so that the increased distance would change an amount ofradiation received by at least the first tissue location or the secondtissue location when at least the first tissue location or the secondtissue location receives a dose of radiation.
 40. The kit of claim 39wherein the instructions provide for introducing the filler intoDenovillier's space.
 41. The kit of claim 39 herein the filler anexpandable device.
 42. The kit of claim 41 wherein the expandable deviceis a balloon.
 43. The kit of claim 39 wherein the instructions describea first tissue location located on a tissue that is a member of thegroup consisting of an ovary, a nerve, a cartilage, a bone, and a brain.44. The kit of claim 39 wherein the instructions describe the firsttissue location as being associated with the rectum and the secondtissue location is being associated with the prostate gland.
 45. The kitof claim 39 wherein the filler comprises a member of the groupconsisting of alginate, gelatin, fibrin, fibrinogen, albumin,polylactide, polyglycolide, polycaprolactone, poly(alpha-hydroxy acid),polyethylene glycol, thixotropic polymers, thermoreversible polymers,and mixtures thereof.
 46. The kit of claim 39 wherein the fillercomprises at least one therapeutic agent.
 47. The kit of claim 46wherein the at least one therapeutic agent is a member of the groupconsisting of an anti-inflammatory drug, an antibiotic, an antimycotics,a hemostat, a steroid, and an analgesic.
 48. The kit of claim 39 whereinthe filler is biodegradable in vivo in less than approximately 90 days.49. The kit of claim 39 wherein the filler comprises a biocompatible,biodegradable material.
 50. The kit of claim 39 wherein thebiocompatible, biodegradable material comprises an extracellular matrixmolecule.
 51. The kit of claim 39 wherein the biocompatible,biodegradable material consists essentially of collagen, hyaluronicacid, or a mixture of thereof.
 52. The kit of claim 39 wherein thefiller comprises at least one polysaccharide.
 53. The kit of claim 39wherein the at least one polysaccharide is hyaluronic acid.
 54. The kitof claim 39 wherein the filler further comprises a member of the groupconsisting of a degradation inhibitor, a radio opaque marker, and anosmotic agent that causes water to become associated with the fillermaterial by osmosis.
 55. The method of claim 39 wherein the fillerfurther comprises a buffering agent.
 56. The kit of claim 39 furthercomprising a device for delivering the filler.
 57. The kit of claim 39wherein the device for delivering the filler comprises a syringe. 58.The kit of claim 39 wherein the instructions relate administration ofthe filler to radiation doses received by the first tissue location, thesecond tissue location, or both the first tissue location and the secondtissue location.
 59. The kit of claim 39 wherein the filler comprises asynthetic polymer.
 60. The kit of claim 39 wherein the filler has avolume in the range of 10 to 200 cubic centimeters after beingintroduced into a patient.
 61. The kit of claim 39 wherein the fillerhas a volume in the range of 5 to 400 cubic centimeters after beingintroduced into a patient.